This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT HYPOTHESIS The overall objectives of this dose finding study are to obtain preliminary information on the safety, tolerability, and pharmacokinetics of TPV/r in the pediatric and adolescent age groups. The study design for this protocol will incorporate well-defined pharmacokinetic endpoints to ensure dose optimization in this population. The initial pediatric TPV/r doses selected for this trial (290 mg/m2 TPV+115 mg/m2 ritonavir b.i.d. and 375 mg/m2 TPV + 150 mg/m2 ritonavir b.i.d.) are conservative, allometrically scaled estimates derived from adult data showing that a well-tolerated and safe dose of 500 mg TPV + 200 mg ritonavir b.i.d. results in median, steady-state trough TPV plasma concentrations (C min) at or above 20uM (10 times the protein-adjusted target IC90 for PI-resistant HIV strains) for more than 77% of patients (B1 Study 1182.52). Body surface area dosing of TPV and ritonavir will be used in this study to reduce potential interindividual pharmacokinetic variability that could result from the compound's extensive plasma protein binding and low volume of distribution. SPECIFIC AIMS The primary objective of this study is to determine the safety and tolerability of tipranavir oral formulation and soft gelatin capsules together with low-dose ritonavir in HIV-infected children and adolescents and to provide information concerning the pharmacokinetic characteristics of tipranavir and ritonavir in this age group. The secondary objective of this study is the determination of the dose of TPV/r in children and adolescents between 2 and 18 years of age required for an adult equivalent systemic exposure of TPV/r 500 mg / 200 mg. PRIMARY ENDPOIN(S) The primary endpoint for this study is the assessment of safety and tolerability of TPV oral formulation using adverse events and significant changes in baseline laboratory measurements (graded with the DAIDS standardized Toxicity Table for Grading Severity of Pediatric [>3 months] Adverse Experiences.) SECONDARY ENDPOINT(S) The key secondary endpoints that will be assessed at both the interim and final analyses for this study are: 1. Determination of TPV and ritonavir pharmacokinetic parameters at steady-state (Cmax, Cp0, Cp10h, Cp12h, AUC0-10h, AUC0-12h, tmax, CL, V, t1/2, and relative bioavilibility of TPV liquid formulation and TPV soft elastic capsules [SEDDS formulation]). Other secondary endpoints include: 2. Proportion of patients reaching and maintaining a viral load<400 copies/mL at Week 24.3 Change in mean CD4 count from baseline to Week 24.4. Assessment of patient compliance with administration of study medication. 5. Time to treatment failure as defined in Section 5.1.2. The therapeutic concept of treating HIV positive patients with a combination of three or more antiretroviral agents in order to reduce plasma HIV RNA levels to undetectable levels has resulted in a substantial reduction in morbidity and mortality from AIDS [R00-1327]. Failing therapy is frequently associated with the development of mutations in the HIV genome that confer resistance to one or more antiretroviral agents. Consequently, there is an increasing population of HIV positive patients who are infected with HIV strains that are resistant to multiple antiretroviral drugs. There is a need for new agents that do not share resistance profiles with existing drugs. The management of pediatric HIV infection with protease inhibitor-containing combination therapy has become a standard of care, particularly for those children with previous antiretroviral treatment and more advanced disease [R02-1305]. In general, less is known about the pharmacologic behavior of this class of drugs in children than adults. Physiologic and metabolic differences between adults and children make it difficult to predict the pediatric pharmacokinetic and pharmacodynamic characteristics of protease inhibitors from available adult data. Drug dose and interval modifications for children are often necessary to achieve and maintain the steady-state plasma concentrations shown to be safe and effective in adults. Protease inhibitors share common metabolic pathways, and pharmacokinetic drug-drug interactions can be exploited to enhance the drug exposures in children in a fashion similar to that employed in adults [R02-1306]. The combination of two protease inhibitors together with other antiretrovirals is therefore an increasingly common therapeutic approach in adults and is rapidly becoming part of the pediatric treatment paradigm as well [R02-1143]. Although the effects of significant drug-drug interactions between different compounds are well described in adults, little is known about the pharmacokinetic impact of this strategy in pediatric HIV-positive patients.